Evidence for a role of NF-kappaB in the survival of hematopoietic cells mediated by interleukin 3 and the oncogenic TEL/platelet-derived growth factor receptor beta fusion protein.

Abstract

Interleukin 3 (IL-3) and other hematopoietic cytokines transduce signals that stimulate DNA synthesis and cell survival. In certain chronic myelomonocytic leukemias, a TEL/platelet-derived growth factor receptor beta (PDGFRbeta) fusion protein is produced as a consequence of the t(5;12) translocation. It contains the amino terminus of the transcription factor TEL fused to the transmembranous and cytoplasmic domains of the PDGFRbeta. It is oncogenic as it substitutes for IL-3, thus promoting cell growth and preventing apoptotic cell death. The mechanism by which TEL/PDGFRbeta generates survival signals remains undefined. Here, we report that both IL-3 and TEL/PDGFRbeta initiate a signaling cascade that leads to the activation of the transcriptional factor NF-kappaB. In fact, either cytokine deprivation of IL-3-dependent Ba/F3 cells or exposure of TEL/PDGFRbeta-expressing cells to the specific inhibitor of the PDGFR tyrosine kinase, CGP53716, caused a strong decrease in NF-kappaB activity followed by extensive cell death. Further, treatment with the proteasome inhibitor Z-IE(O-t-Bu)A-leucinal suppressed IL-3 and TEL/PDGFRbeta-dependent survival. The same result was seen upon overexpression of an unphosphorylable form of IkappaBalpha. Because both conditions inactivate NF-kappaB by preventing its translocation into the nucleus, that process seems to be essential for cell survival in response to IL-3 and TEL/PDGFRbeta. Moreover, overexpression of a dominant-negative mutant of the protooncogene c-Myc, a downstream target of NF-kappaB, had a similar effect. We conclude that NF-kappaB plays an important role in maintaining cell survival in response to IL-3 and TEL/PDGFRbeta and that c-Myc may be a downstream effector mediating this effect.

• Authors: F Besançon, A Atfi, C Gespach, Y E Cayre, M F Bourgeade
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 95 Issue 14 Pg. 8081-6 (Jul 07 1998) ISSN: 0027-8424 [Print] United States
• PMID: 9653143 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CGP 53716
• DNA-Binding Proteins
• ETS translocation variant 6 protein
• Enzyme Inhibitors
• Interleukin-3
• NF-kappa B
• Oncogene Proteins, Fusion
• Proto-Oncogene Proteins c-ets
• Pyridines
• Pyrimidines
• Repressor Proteins
• Transcription Factors
• Receptor, Platelet-Derived Growth Factor beta
• Receptors, Platelet-Derived Growth Factor

Topics

• Animals
• Apoptosis (drug effects)
• Cell Survival (drug effects)
• DNA-Binding Proteins (genetics)
• Enzyme Inhibitors (pharmacology)
• Hematopoietic Stem Cells (drug effects, pathology, physiology)
• Interleukin-3 (pharmacology)
• Mice
• Mutation
• NF-kappa B (physiology)
• Oncogene Proteins, Fusion (genetics, pharmacology)
• Proto-Oncogene Proteins c-ets
• Pyridines (pharmacology)
• Pyrimidines (pharmacology)
• Receptor, Platelet-Derived Growth Factor beta
• Receptors, Platelet-Derived Growth Factor (genetics)
• Repressor Proteins
• Signal Transduction (drug effects, physiology)
• Transcription Factors (genetics)
• Transfection